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Inhibition of Eukaryotic Translation by the Antitumor Natural Product Agelastatin A.

McClary B, Zinshteyn B, Meyer M, Jouanneau M, Pellegrino S, Yusupova G, Schuller A, Reyes JCP, Lu J, Guo Z, Ayinde S, Luo C, Dang Y, Romo D, Yusupov M, Green R, Liu JO
Cell Chem Biol 24 605-613.e5 (2017)
Cited: 22 times
EuropePMC logo PMID: 28457705

Abstract

Protein synthesis plays an essential role in cell proliferation, differentiation, and survival. Inhibitors of eukaryotic translation have entered the clinic, establishing the translation machinery as a promising target for chemotherapy. A recently discovered, structurally unique marine sponge-derived brominated alkaloid, (-)-agelastatin A (AglA), possesses potent antitumor activity. Its underlying mechanism of action, however, has remained unknown. Using a systematic top-down approach, we show that AglA selectively inhibits protein synthesis. Using a high-throughput chemical footprinting method, we mapped the AglA-binding site to the ribosomal A site. A 3.5 Å crystal structure of the 80S eukaryotic ribosome from S. cerevisiae in complex with AglA was obtained, revealing multiple conformational changes of the nucleotide bases in the ribosome accompanying the binding of AglA. Together, these results have unraveled the mechanism of inhibition of eukaryotic translation by AglA at atomic level, paving the way for future structural modifications to develop AglA analogs into novel anticancer agents.

Reviews - 5mei mentioned but not cited (1)

  1. Inhibition of the Eukaryotic 80S Ribosome as a Potential Anticancer Therapy: A Structural Perspective. Pellegrino S, Terrosu S, Yusupova G, Yusupov M. Cancers (Basel) 13 4392 (2021)

Articles - 5mei mentioned but not cited (1)

  1. A Virtual Screening Platform Identifies Chloroethylagelastatin A as a Potential Ribosomal Inhibitor. Caulfield TR, Hayes KE, Qiu Y, Coban M, Seok Oh J, Lane AL, Yoshimitsu T, Hazlehurst L, Copland JA, Tun HW. Biomolecules 10 E1407 (2020)


Reviews citing this publication (4)

  1. Roadblocks and resolutions in eukaryotic translation. Schuller AP, Green R. Nat Rev Mol Cell Biol 19 526-541 (2018)
  2. Along the Central Dogma-Controlling Gene Expression with Small Molecules. Schneider-Poetsch T, Yoshida M. Annu Rev Biochem 87 391-420 (2018)
  3. A Quick Guide to Small-Molecule Inhibitors of Eukaryotic Protein Synthesis. Dmitriev SE, Vladimirov DO, Lashkevich KA. Biochemistry (Mosc) 85 1389-1421 (2020)
  4. The Recurring Roles of Chlorine in Synthetic and Biological Studies of the Lissoclimides. Pak BS, Supantanapong N, Vanderwal CD. Acc Chem Res 54 1131-1142 (2021)

Articles citing this publication (16)

  1. High-Resolution Ribosome Profiling Defines Discrete Ribosome Elongation States and Translational Regulation during Cellular Stress. Wu CC, Zinshteyn B, Wehner KA, Green R. Mol Cell 73 959-970.e5 (2019)
  2. Endogenous rRNA Sequence Variation Can Regulate Stress Response Gene Expression and Phenotype. Kurylo CM, Parks MM, Juette MF, Zinshteyn B, Altman RB, Thibado JK, Vincent CT, Blanchard SC. Cell Rep 25 236-248.e6 (2018)
  3. Tetracyclines Modify Translation by Targeting Key Human rRNA Substructures. Mortison JD, Schenone M, Myers JA, Zhang Z, Chen L, Ciarlo C, Comer E, Natchiar SK, Carr SA, Klaholz BP, Myers AG. Cell Chem Biol 25 1506-1518.e13 (2018)
  4. Assaying RNA structure with LASER-Seq. Zinshteyn B, Chan D, England W, Feng C, Green R, Spitale RC. Nucleic Acids Res 47 43-55 (2019)
  5. Understanding the role of intermolecular interactions between lissoclimides and the eukaryotic ribosome. Pellegrino S, Meyer M, Könst ZA, Holm M, Voora VK, Kashinskaya D, Zanette C, Mobley DL, Yusupova G, Vanderwal CD, Blanchard SC, Yusupov M. Nucleic Acids Res 47 3223-3232 (2019)
  6. Natural product 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose is a reversible inhibitor of glyceraldehyde 3-phosphate dehydrogenase. Li W, Liao LP, Song N, Liu YJ, Ding YL, Zhang YY, Zhou XR, Sun ZY, Xiao SH, Wang HB, Lu J, Zhang NX, Jiang HL, Chen KX, Liu CP, Zheng J, Zhao KH, Luo C. Acta Pharmacol Sin 43 470-482 (2022)
  7. Ataluren binds to multiple protein synthesis apparatus sites and competitively inhibits release factor-dependent termination. Huang S, Bhattacharya A, Ghelfi MD, Li H, Fritsch C, Chenoweth DM, Goldman YE, Cooperman BS. Nat Commun 13 2413 (2022)
  8. A Glucose-Triptolide Conjugate Selectively Targets Cancer Cells under Hypoxia. Datan E, Minn I, Xu P, He QL, Ahn HH, Yu B, Pomper MG, Liu JO. iScience 23 101536 (2020)
  9. Synthesis and Evaluation of Agelastatin Derivatives as Potent Modulators for Cancer Invasion and Metastasis. Antropow AH, Xu K, Buchsbaum RJ, Movassaghi M. J Org Chem 82 7720-7731 (2017)
  10. Total synthesis of (-)-agelastatin A: an SH2' radical azidation strategy. Tsuchimochi I, Kitamura Y, Aoyama H, Akai S, Nakai K, Yoshimitsu T. Chem Commun (Camb) 54 9893-9896 (2018)
  11. Orthogonally Protected Diaminocyclopentenones as Synthons: Total Synthesis of (±)-Agelastatin A. Gomes RFA, Vale JR, Pereira JG, Afonso CAM. Org Lett 25 4188-4192 (2023)
  12. Using DMS-MaPseq to uncover the roles of DEAD-box proteins in ribosome assembly. Liu X, Huang H, Karbstein K. Methods 204 249-257 (2022)
  13. Osteopontin promotes age-related adipose tissue remodeling through senescence-associated macrophage dysfunction. Sawaki D, Zhang Y, Mohamadi A, Pini M, Mezdari Z, Lipskaia L, Naushad S, Lamendour L, Altintas DM, Breau M, Liang H, Halfaoui M, Delmont T, Surenaud M, Rousseau D, Yoshimitsu T, Louache F, Adnot S, Henegar C, Gual P, Czibik G, Derumeaux G. JCI Insight 8 e145811 (2023)
  14. Synthesis of Agelastatin A and Derivatives Premised on a Hidden Symmetry Element Leading to Analogs Displaying Anticancer Activity. Xue H, Svatek H, Bertonha AF, Reisenauer K, Robinson J, Kim M, Ingros A, Ho M, Taube J, Romo D. Tetrahedron 94 132340 (2021)
  15. The N-Alkylation of Agelastatin A Modulates Its Chemical Reactivity. D'Ambrosio M. Molecules 28 6821 (2023)
  16. Uncovering the Cellular Target of Agelastatin A. Park Y, Liau BB. Cell Chem Biol 24 542-543 (2017)


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